Virostatically effective substituted 3-alkenyl-5-ethyl uracil compounds

ABSTRACT

HIGHLY EFFECTIVE VIROSTATIC AGENTS ARE SUBSTITUTED 5-ETHYL URACIL COMPOUNDS WHICH HAVE ALKENYL WITH 3 TO 6 CARBON ATOMS IN 3-POSITION AND MAY BE SUBSTITUTED IN 1POSITION BY ALKYL WITH 1 TO 4 CARBON ATOMS, CYCLOALKYL, ARYL, OR ARALKYL AND IN 4-POSITION BY HALOGEN. EXAMPLES OF SUCH COMPOUNDS ARE 1,5-DIETHYL-3-ALLYL-4-CHLORO URACIL, 1-METHYL-3-ALLYL OR CROTYL-4-CHLORO-5-ETHYL URACILS, 1METHYL OR ETHYL-3-ALLYL OR CROTYL-5-ETHYL URACILS. THEY ARE PREFERABLY OBTAINED BY ALKENYLATION IN 3-POSITION OF THE CORRESPONDING 5-ETHYL URACIL COMPOUNDS WHICH HAVE IN 3-POSITION HYDROGEN. THEY ARE PREFERABLY TOPICALLY APPLIED TO THE VIRUS-AFFECTED AREAS OF THE BODY IN THE FORM OF SOLUTIONS, OINTMENTS, POWDERS, SPRAYS, OR THE LIKE WHICH CONTAIN BETWEEN ABOUT 0.5% AND ABOUT 50% THEREOF.

United States Patent Otfice Patented Feb. 2, 1971 US. Cl. 260-260 12Claims ABSTRACT OF THE DISCLOSURE Highly effective virostatic agents aresubstituted S-ethyl uracil compounds which have alkenyl with 3 to 6carbon atoms in 3-position and may be substituted in 1- position byalkyl with 1 to 4 carbon atoms, cycloalkyl, aryl, or aralkyl and in4-position by halogen. Examples of such compounds are1,5-diethyl-3-allyl-4-chloro uracil, 1-methyl-3-allyl orcrotyl-4-chloro-5-ethyl uracils, 1- methyl or ethyl-3-allyl orcrotyl-S-ethyl uracils. They are preferably obtained by alkenylation in3-position of the corresponding S-ethyl uracil compounds which have in3-position hydrogen. They are preferably topically applied to thevirus-affected areas of the body in the form of solutions, ointments,powders, sprays, or the like which contain between about 0.5% and about50% thereof.

BACKGROUND OF THE INVENTION 1) Field of the invention The presentinvention relates to new and valuable uracil compounds and moreparticularly to virostatically effective S-ethyl uracil compounds, to aprocess of their manufacture, to pharmaceutical compositions containingsame, and to a method of using same in the therapy of virus infections.

(2) Description of the prior art -alkyl substituted uracil compounds areknown (M. Muraoka, A. Takada, and T. Ueda Keio J. Med., vol. 11 (1962)page 95; see Chem. Abstracts, vol. 57 (1962), page 171921)). Thesecompounds were found to be virostatically ineffective. 1,5-disubstituteduracil compounds have also no virostatic activity.

SUMMARY OF THE INVENTION It is one object of the present invention toprovide highly virostatically effective compounds of the uracil groupwhich are characterized by being substituted in 3- position or,respectively, in 3-, and 4-position and may be substituted in l-positionand which have ethyl in 5- position.

Another object of the present invention is to provide a simple andeffective process of producing such substituted S-ethyl uracilcompounds.

A further object of the present invention is to provide virostaticallyeffective compositions containing such substituted S-ethyl uracilcompounds as active ingredients.

Still another object of the present invention is to provide a method oftreating patients affected by virus infections with such disubstitutedS-ethyl uracil compounds.

Other objects of the present invention and advantageous features thereofwill become apparent as the description proceeds.

In principle the virostatically effective S-ethyl uracil compoundsaccording to the present invention are compounds of the followingFormula I:

o=o CX R2 (1) In said formula R indicates straight chain or branchedalkyl with 1 to 4 carbon atoms, preferably methyl or ethyl, cycloalkyl,aryl, or aralkyl, which alkyl, aryl, or aralkyl may be substituted;

R indicates straight chain or branched alkenyl with 3 to 6 carbon atoms,preferably allyl or crotyl; and

X indicates hydrogen or halogen, preferably chlorine.

A preferred process of producing such compounds comprises reactingS-ethyl uracil compounds of Formula II 0 II o wherein R and X representthe same substituents as indicated above, with an alkenyl halogenide,such as al1ylbromide, in the presence of a basic agent capable ofbinding acids, for instance, potassium carbonate, in a suitable solventor solvent mixture or even without solvent whereby the alkenylhalogenide serves as solvent.

phenyl alanine. In addition thereto they are of surprisingly lowtoxicity.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examples serve toillustrate the present invention without, however, limiting the samethereto.

Example 1 20.3 g. of 1,5-diethyl-4-chloro uracil are heated under refluxwith 36.3 g. of allylbromide and 16.6 g. of freshly calcined potassiumcarbonate in 120 cc. of dried acetone and cc. of dried dimethylformamidefor 2.4 hours. Care is taken that moisture is excluded during thereaction. After cooling, the reaction mixture is filtered to removesolid matter. The mixture of solvents and excess allylbromide isdistilled off in a vacuum and the residue is subjected to fractionaldistillation in a vacuum. The resulting 1,5-diethyl-3-allyl-4-chlorouracil has a boiling point of -120" C./O.1 mm. Hg, refractive index 4Example 10.0 g. of 1-methyl-3-crotyl-4-chloro-S-ethyl uracil areincorporated into an ointment base consisting of 3.0 g. of cetylalcohol, 5.0 g. of anhydroud lanolin, and 82.0 g.

5 of white petrolatum. The resulting ointment is applied to thevirus-affected parts of the body.

TABLE I Analysis, percent Boiling point Calculated Found EmpiricalMolecular Example No. R1 R2 X C. mm. Hg formula weight C H N C H NCHZCH=OH2 01 140-141 0.3 CmHraClNzOz 228.69 62.52 5.73 12. 52.57 6.6912.22 CH2CH=CHCH 01 145447 0.4 CnHrsClNzOz 242.70 54.44 6.23 11. 54 54.42 6.30 11.54 CH20H=GH H 138 0.3 C11H15N2O2 208.26 63.43 7.74 13. 63.387.78 13.49 CzH5 CHz-CH=CHCH H 150-152 0.2 CrzHrsNzOz 222.29 64.84 8.1612.60 64. 78 8.24 12.59

In place of the starting uracil compounds used in the Example 11preceding examples, there may be employed equimolecu- 20 lar amounts,for instance, of isopropyl-4-chloro-5-ethyl uracil,1-n-butyl-4-bromo-5-ethyl uracil, 1-phenyl-4-iodo- S-ethyl uracil,1-p-tolyl-4-chloro-S-ethyl uracil, l-benzyl- 4-chloro-5-ethyl uracil,4-chloro-5-ethyl uracil, l-cyclohexyl-4-chloro-5-ethyl uracil, and thelike compounds while otherwise the procedure is the same as describedhereinabove.

In place of the alkenyl halogenides used as the other reaction componentin the preceding examples, there may be employed equimolecular amounts,for instance, of 1-chloro-2-pentene, l-bromo-Z-hexene,1-chl0ro-3-methyl-2-butene, 1=bromo-2,3-dimethyl-2-butene, 1-chloro-3-butene, and the like compounds while otherwise the procedure is the sameas indicated above.

As stated hereinabove, the new substituted S-ethyl uracil compounds aretopically applied to the Virus-infected areas of the body in the form ofsolutions, emulsions, creams, ointments, powders, sprays, and the likepreparations. The amount of the active agent in such pharmaceuticalpreparations may vary. Amounts between 0.5% and and even more may beadmixed to the pharmaceutical excipients, ointment bases, solvents, andthe like. Preferred amounts of the virostatically active agent in suchpreparations are amounts between about 1.0% and 10.0%.

The following examples serve to illustrate the preparation of suitablepharmaceutical preparations according to the present invention without,however, being limited thereto.

Example 6 10.0 g. of 1,5-diethyl-3-allyl-4-chloro uracil are dissolvedin 10.0 g. of propylene glycol and 80 g. of 50% ethanol. The resultingsolution is repeatedly applied to the virus aiTected area of the skin orto the lips.

Example 7 50.0 g. of 1,S-diethyl-3-allyl-4-chloro uracil are dissolvedin 50.0 g. of dimethylsulfoxide. The resulting solution is repeatedlyapplied to the virus-affected areas of the body.

Example 8 1.0 g. of 1,5-diethyl-3-allyl-4-chloro uracil is dissolved in3.0 g. of the polyoxy ethylene ester of castor oil sold under thetrademark ORPE by Fabenfabriken Bayer of Opladen, Germany, and 96 g. ofphysiological (0.9%) sodium chloride solution is added. The resultingmixture is applied to the virus affected parts of the body.

Example 9 0.5 g. of 1-methyl-3-allyl-4-chloro-5-ethyl uracil isdissolved in 99.5 g. of the liquid saturated fatty alcohol mixtureconsisting mainly of 2-octyl dodecanol and sold under the trademarkEutanol G by Deutsche Hydrierwerke G.m.b.H. of Duesseldorf, Germany.

5.0 g. of 1-methyl-3-allyl-5-ethyl uracil are intimately mixed with 10.0g. of glycine, 10.0 g. of lactose, and g. of finely divided silicic acidsold under the trademark Aerosil are intimately mixed with each other toyield a virostatically eflective powder.

EXAMPLE 12 1.0 g. of l-methyl-crotlyl-S-ethyl uracil are mixed with 5 .0g. of ethanol and enclosed into a spray container with 94.0 g. of apropellant such as trichlorofluoro methane. The resulting preparation isapplied by spraying to virusaffected parts of the body.

Example 13 5 g. of 1,5-diethyl3-allyl-4-chloro uracil and 5 g. of anon-ionogenic emulsifier sold under the trademark Cremophor EL byBadische Anilin- & Soda-Fabrik of Ludwigshafen, Germany, which is acondensation prodnet of ethylene oxide with castor oil, are intimatelymixed with cc. of physiological (0.9%) sodium chloride solution. Theresulting mixture is repeatedly applied to the virus-affected parts ofthe body.

Example 14 2 g. of 1,S-diethyl-3-allyl-4-chloro uracil are emulsifiedwith 2 g. of Tween 60 sold by Atlas Powder Company of Wilmington andbeing a polyoxyethylene sorbitan mono-stearate, 6 g. of Arlacel 60, soldby Atlas Powder Company of Wilmington, Del., and being a sorbitanmono-stearate, 10 g. of stearic acid, and 4 g. of Witocan H, sold byChemische Werke Witten G.m.b.H. of Witten (Ruhr), Germany, which is amixture of fatcontaining saturated fatty acids with 12 to 18 carbonatoms, in 76 cc. of distilled water. The resulting composition hasproved of value in the treatment of virus infections.

Example 15 10 g. of 1,S-diethyl-3-allyl-4-chloro uracil are incorporatedinto an ointment of 10' g. petrolatum (Vaseline), 40 g. of anhydrouslanolin, 7 g. of liquid petrolatum (liquid parafiin), and 33 cc. ofwater. The resulting ointment is useful for topical application.

Of course, other solutions, lotions, ointments, powders, sprays, and thelike compositions may be prepared with other solvents, ointment bases,excipients, and the like.

The composition containing the above mentioned substituted S-ethyluracil compounds according to the present invention are useful fortopical application to the virus-affected parts of the human body. Theymay be applied not only to the skin of the patient but also to mucousmembranes, such as the mucous membranes of the mouth and of the genitalorgans.

UTILITY The virostatic activity of the substituted S-ethyl uracilcompounds according to the present invention has been demonstrated invitro in tissue cultures and in vivo on the rabbits eye according to themethod of Kaufman et al. Arch. Ophthalm., vol. 67 (1962), page 583.These tests have shown that said compounds are highly effective againstDNA-viruses such as herpes, vaccinia, varicella virus as well as againstRNA-viruses, such as foot-andmouth-disease, Sindbis virus and others.

Clinical tests have been carried out especially with1,5-diethyl-3-allyl-4-chloro uracil which was used in herpes diseases ofthe skin and the mucosa. The following Table II shows the resultsachieved by a treatment:

(a) with the composition according to Example 6, (b) with thecomposition according to Example 7, and (c) with the compositionaccording to Example 8.

The preparations of these examples were applied externally by means of aswab stick to the respective parts of the body in the beginning of thetreatment five times daily and later once to five times daily for atotal period of from one day to five days. It may be mentioned that onlypatients who were suffering for more than three years from such herpesinfections were treated with the preparations according to the presentinvention.

TABLE II Patients Complete Improve- Irrita- Ex. Virus infection treatedcure ment tion 6- Herpes labialis. 8 6 2 Herpes solemn. 1 1 0 Herpeslabialis 5 2 2 1 7 Herpes simplex 6 3 1 2 7 Herpes genitalia" 2 2 0 07.. Stomatitis aphthosau 2 1 1 0 8 Herpes labialt's 8 6 2 0 Herpessimplex- 3 2 1 0 8 herpes genitalia. l 1 0 0 8 Stomatt'tt's aphthosan 20 2 0 Total 38 23 12 3 The rate of complete cure in these preliminaryclinical tests thus is at least 60%. Treatment with the preparationsaccording to the present invention has the advantage that the herpesblisters, for instance, of Herpes simplex became disiccated and healedwithin one to five days while without such a treatment healing requiredeight to ten days. It is to be assumed that irritation is not caused bythe compounds of this invention but by the solvent dimethyl sulfoxide,especially since dimethyl sulfoxide applied without medicament to freshHerpes blisters causes a burning sensation.

Of course, many changes and variations in the starting materials,unsaturated halogenides, and basic acid-burning agents used, in thereaction conditions, temperature, and duration, in the preparation andcomposition of pharmaceutical preparations containing the substitutedS-ethyl uracil compounds of the present invention, in the mode ofadministration and the amounts administered and the like may be made bythose skilled in this art in accordance with the principles set forthherein and in the claimed annexed hereto.

I claim:

1. A substituted S-ethyl uracil compound of the formula:

wherein R is a member selected from the group consisting of alkyl with 1to 4 carbon atoms, cyclohexyl, phenyl, tolyl, and benzyl;

R is a member selected from the group consisting of allyl and crotyl;and

X is a member selected from the group consisting of hydrogen andhalogen. 21. A substituted S-ethyl uracil compound of the formu a:

methyl and ethyl; R is a member selected from the group consisting ofallyl and crotyl; and X is a member selected from the group consistingof hydrogen and halogen. 3. The compound as defined in claim 1, whereinX is chlorine.

4. The compound as defined in claim 1, wherein R is methyl.

5. The compound as defined in claim 1, wherein R is ethyl.

6. The compound as defined in claim 1, wherein R is allyl.

7. The compound as defined in claim 1, wherein R is crotyl.

8. The compound as defined in claim 1, wherein R is ethyl, R is allyl,and X is chlorine, said compound being 1,5-diethyl-3-allyl-4-chlorouracil.

9. The compound as defined in claim 1, wherein R is methyl, R is allyl,and X is chlorine, said compound being1-methyl-3-allyl-4-chloro-5-ethyl-uracil.

10. The compound as defined in claim 1, wherein R is methyl, R iscrotyl, and X is chlorine, said compound being1-methyl-3-crotyl-4-chloro-5-ethyl uracil.

11. The compound as defined in claim 1, wherein R is ethyl, R is allyl,and X is hydrogen, said compound being 1,5-diethyl-3-allyl uracil.

12. The compound as defined in claim 1, wherein R is ethyl, R is crotyl,and X is hydrogen, said compound being 1,5-diethyl-3-crotyl uracil.

References Cited UNITED STATES PATENTS 2/1966 Luckenbaugh et al. 260-2607/1967 Luckenbaugh 260-260 US. Cl. X.R. 424-251

